The present invention relates to low density oral pharmaceutical compositions in unit dosage form suitable for swallowing comprising solid Colloidal Bismuth Subcitrate.
Solid Colloidal Bismuth Subcitrate ("CBS"; Trademark De-Nol.RTM. of Gist-brocades N.V.) is the product of European Patent 0,075,992, corresponding to U.S. Pat. No. 4,801,608. It is also the active ingredient of British Patent 1,478,742. According to these specifications, CBS can be formulated into pharmaceutical compositions in solid dosage form for oral administration, such as tablets and capsules. Up to now only the tablet form (both chewable and swallowable tablets) has been realized and it is marketed in many countries.
The currently used swallowable tablet form of CBS has already been given to hundreds of thousands of patients and its clinical efficacy and safety are firmly established. However, recently there have been reports of a transient sharp peak of bismuth blood level in humans after the ingestion of this CBS-containing swallowable tablet, t.sub.max around 30 minutes (see C. U. Nwokolo et al, Aliment. Pharmacol. Therap., 3, 1989, 29-39). Since the therapeutic action of CBS is believed to be localized in the gastrointestinal tract, even a transient peak of bismuth blood level does not appear to serve any useful purpose and it is therefore desirable to minimize bismuth blood levels if possible.
It has been discovered that this currently used tablet form (having a density greater than 1 g/ml), in vitro in liquid acidic medium, has a tendency to sink to the bottom of the liquid and dissolve by first forming liquid CBS solution rather than the desired insoluble bismuth precipitate. By contrast, unit dosage forms (as according to the present invention) which are less dense than the current tablet form and also less dense than the acidic medium (approximately 1 g/ml) do not form this initial CBS liquid but rather quickly forms the desired insoluble bismuth precipitate. Interestingly, when these low density unit dosage forms are weighted to the bottom of the test liquid, again the CBS initially liquifies.
A low packing density of oral dosage units as specified above is contrary to the current tendency in the art of pharmaceutical production, which is to concentrate the oral dosage units, e.g. by compressing the contents of oral capsules to a high density (see Hard Capsules, Development and Technology, Ed. K. Ridgway 1987, chapter 9, G. C. Cole, pp. 92-103).
That the low density unit dosage form of the present invention in fact substantially reduces bismuth blood levels as predicted by these different in vitro characteristics has been confirmed by in vivo testing. The oral dosage units of the present invention, when compared to swallowable tablets comprising the same formula and dosage of CBS but with a higher density, were found to give not only a lower maximal blood plasma bismuth level (C.sub.max), but also a lower blood plasma bismuth rise (AUC) and a lower bismuth excretion in the urine. Therefore, systemic bismuth absorption after ingestion of the dosage units of the present invention has proved to be lower than after ingestion of the prior swallowable tablets. This is contrary to what one might expect--that less dense and thereby more dispersible material would lead to more rapid dissolution and consequently to greater absorption than compressing to higher density the same material.
Thus, the oral dosage units of the present invention surprisingly give peak bismuth plasma levels and a total bismuth absorption which are lower than that of the denser dosage units.
An object of the present invention therefore is to provide an oral dosage unit suitable for swallowing comprising CBS in a therapeutically effective amount which substantially reduces bismuth absorption and thereby the above described peak in the bismuth blood levels.
This and other objects of the present invention will become readily apparent from the detailed description which follows.
All percentages and ratios used herein are by weight, and all measurements made at 25.degree. C., unless otherwise specified.